Dolastatin-10 induces polyploidy, telomeric associations and apoptosis in a murine melanoma cell line.
Our purpose was to study the effects of dolastatin-10 (Dol-10) on chromosome morphology, telomeric associations, induction of polyploidy and cell death in a metastatic murine melanoma cell line, K1735 clone X-21. Murine melanoma cells were treated with various concentrations (10 ng/ml, 100 ng/ml and 1000 ng/ml) of Dol-10 for 4, 24 and 72 h continuously and harvested immediately without recovery. In another set of experiments, cells were treated for 4 h with the same concentrations, washed with prewarmed medium and then allowed to recover in drug-free medium for 24 h and subsequently harvested. Our preliminary results indicated: i) a drug-mediated increase in the frequency of metaphases, with telomeric associations resulting in multicentric and ring configurations; ii) induction of clumping in metaphase chromosomes; iii) induction of polyploidy as a result of endoreduplication; iv) formation of micronucleated cells; and v) induction of cell death. These observations indicated that Dol-10 could be a potent antineoplastic drug against malignant melanoma. In addition to its reported interaction with cell microtubules, the mechanism of action of Dol-10 may be mediated through the loss of telomeric repeats and induction of chromosome aberrations.
Pathak
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Cellular Genetics Laboratory, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 181, Houston, TX 77030, USA.
Multani
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Ozen
M
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Richardson
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Newman
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RA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D017404:In Situ Hybridization, Fluorescence; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D011123:Polyploidy; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D016615:Telomere / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D047630:Depsipeptides; D009842:Oligopeptides; C064570:dolastatin 10